Urine screening for metabolic disorders

Overflow disorder

Results from the disruption of a normal metabolic pathway that causes increased plasma concentrations of the nonmetabolized substances.

fat, protein, and carbohydrates

overflow disorder is associated with metabolic disturbances of?

inborn error of metabolism

• is the disruption of enzyme function caused by failure to inherit the gene to produce a particular enzyme.

• The missing enzyme is specifically used for the complete breakdown of a specific substance.

Renal disorder

• is caused by malfunctions in the tubular reabsorption mechanism.

• The appearance of abnormal metabolic substances in urine is caused by problems in tubular reabsorption.

tandem spectrophotometry (MS/MS)

Newborn screening test is performed using?

24 to 48 hours

In newborn screening test, blood is collected within how many hours after birth?

1. Phenylalanine-Tyrosine Disorders

2. Branched-Chain Amino Acid Disorders

Amino acid disorders:

1. Phenylketonuria (PKU)

2. Tyrosyluria 

3. Melanuria

4. Alkaptonuria

Phenylalanine-tyrosine disorder:

1. Maple Syrup Urine Disease

2. Organic Acidemias

Branched-chain amino acid disorders:

1. Indicanuria

2. 5-hydroxyindolacetic acid

Tryptophan disorder:

1. Cystinosis

2. Homocystinuria

Cysteine disorders:

Phenylketonuria

• It occurs in 1 of every 10,000 to 20,000 births.

• Autosomal recessive inherited disorder.

• It is caused by the absence of phenylalanine hydroxylase.

• plasma phenylalanine, phenylpyruvic acid

• urinary phenylpyruvic acid, phenylacetic acid, and phenylalanine

Absence of phenylalanine hydroxylase increases?

• Mental retardation

• Seizures, hyperactivity, developmental delay, and psychiatric disturbances.

• Fair complexion, lighter hair, and eyes.

• Mousy or musty urine and sweat odor.

Clinical features of phenylketonuria:

Ferric Chloride Tube Test

Screening test for phenylketonuria

1. Transitory Hypertyrosinemia

2. Type I Hereditary Tyrosinemia

3. Type II Tyrosinemia (Richner-Hanhart Syndrome)

4. Type III Tyrosinemia

Tyrosyluria includes:

Tyrosyluria

occurs when the abnormal metabolism of tyrosine from the diet or from phenylalanine is abnormal.

Transitory hypertyrosinemia

It occurs in low-birthweight and premature infants as a benign condition.

• Asymptomatic

• Absence of liver or renal disease

• There is no hepatic or renal involvement.

• Elevated plasma tyrosine and phenylalanine (transient and occasionally) levels.

• Elevated urinary tyrosine, p-hydroxyphenyllactic, and p-hydroxylphenylpyruvic acids.

Clinical features of Transitory hypertyrosinemia:

Type I hereditary tyrosinemia

• Autosomal recessive disorder.

• Caused by defects in Fumarylacetoacetate hydrolase (Ia)  and Maleylacetoacetate isomerase (Ib)

• Liver failure

• Hepatoma (late complication)

• Renal dysfunction

• Rickets

• Acute intermittent porphyria-like symptoms

• Phosphaturia

• Glycosuria

Clinical features of Type I hereditary tyrosinemia:

Type II Tyrosinemia (Richner-Hanhart syndrome)

• Autosomal recessive disorder.

• It is caused by a deficiency of tyrosine aminotransferase.

• Elevated urinary phenolic acids.

• Erosions of the cornea, soles, and palms.

Clinical features of Type II Tyrosinemia (Richner-Hanhart syndrome):

Type III Tyrosinemia

• Autosomal recessive disorder.

• It is caused by a deficiency of p-hydroxyphenylpyruvic acid dioxygenase.

Nitroso-Naphthol Test.

Screening test for Tyrosyluria

Melanuria

• Increased urinary melanin.

• Serious finding that indicates proliferation of normal melanin-producing cells (melanocytes), producing a malignant melanoma.

• 5,6-dihyroxyindole is secreted by tumors, which oxidizes to melanogen and then to melanin.

Alkaptonuria

• It is caused by a deficiency of homogentisic acid oxidase.

• Accumulation of homogentisic acid in blood, tissues, and urine.

• Liver disorders.

• Cardiac disorders.

• Urine turns brown-black on standing or with alkaline pH.

Clinical features of Alkaptonuria:

Ochronosis

is a brown pigmentation in cartilage and connective tissue.

• Ferric Chloride Test

• Homogentisic Acid Test

Screening test for Alkaptonuria:

Maple syrup urine disease

• Autosomal recessive disorder.

• It is caused by the failure to inherit the gene for the enzyme (branched-chain α-ketoacid dehydrogenase complex) necessary for oxidative decarboxylation of keto acids.

• Results in keto acid accumulation in the blood and urine.

• Leucine

• Isoleucine 

• Valine

Amino acids affected with maple syrup urine disease:

• Urine with maple syrup odor

• Severe neonatal vomiting

• Seizures

• Stupors

• Irregular respirations

• Hypoglycemia

Clinical features of Maple syrup urine disease: 

2,4-dinitrophenylhydrazine (DNPH) Test

Screening test for Maple syrup urine disease

Isovaleric acidemia

• may be suspected when urine specimens and sometimes even the patient possess a characteristic odor of sweaty feet. This odor is caused by the accumulation of isovalerylglycine due to a deficiency of the enzyme isovaleryl coenzyme A dehydrogenase.

• It leads to the buildup of isovaleric acid and other harmful substances.

Propionic Acidemia

Deficiency of propionyl coenzyme A carboxylase.

Methylmalonyl Acidemia

Methylmalonyl Acidemia

Indicanuria

• In certain intestinal disorders, such as obstruction, the presence of abnormal bacteria, malabsorption syndromes, and Hartnup disease, which is a rare genetic disorder, increased amounts of tryptophan that are ultimately converted to indican.

• The excess indole is reabsorbed from the bloodstream and is circulated in the liver, where it is converted to indican and finally excreted in the urine, causing indicanuria.

Indican

is colorless until it is oxidized to the dye indigo blue by exposure to air, which causes the 5-H, meaning there is blue staining of diapers of infants.

5-Hydroxyidoleacetic acid

Normal physiology:

1. Argentaffin cells produces serotonin from tryptophan.

2. Platelets carry serotonin throughout the body. 

3. The body uses most of the serotonin.

4. 5-HIAA is the main degradation product of serotonin for excretion.

Silver nitroprusside test

Screening test for 5-Hydroxyidoleacetic acid:

Cystinuria

• is a problem with reabsorption

• It is caused by the inability of the renal tubules to reabsorb cystine filtered by the glomerulus.

Cyanide-Nitroprusside Test

Screening test for cystinuria

Cystinosis

• is a problem with metabolism

• It is caused by a defect in the lysosomal membranes that prevents the release of cystine into the cellular cytoplasm for metabolism.

• is inherited in an autosomal recessive disorder, and this is caused by a mutation in the CTNS gene, which is responsible for coding the protein cystinosin.

Nephropathic cystinosis

• There is renal involvement.

• It is subdivided into infantile and late-onset.

Non-nephropathic cystinosis

• There is no renal involvement.

• This is relatively benign.

Homocystinuria

• s caused by the deficiency of cystathionine β-synthase.

• Cystathionine β-synthase is responsible for the formation of cystathionine from homocysteine and serine.

• Homocysteine, when increased, can cause failure to thrive, cataracts, and intellectual disability because homocysteine is neurotoxic. 

• It can also cause thromboembolic problems such as strokes and myocardial infarctions because it can cause platelet aggregation.

Porphyrins

are intermediate compounds in the production of heme.

Porphyrias

is the disorder of porphyrin metabolism.

Inherited porphyrias

It is caused by failure to inherit a gene that produces an enzyme needed in the metabolic pathway.

Acquired porphyrias

• From erythrocytic and hepatic malfunctions or exposure to toxic agents.

• Common causes: lead poisoning, excessive alcohol intake, iron deficiency, chronic liver disease, and renal disease.

Red or port wine color urine after exposure to air.

Indication of porphyria

ALA, porphobilinogen, and uroporphyrin

are the most soluble and readily appear in urine.

• Ehrlich Reaction (Watson-Schwartz Test and Hoesch Test)

• Fluoresence under UV (550 – 600nm)

Screening test for porphyria

Ehrlich Reaction

• is for the detection of ALA, porphobilinogen, and urobilinogen.

• reagent: p-dimethylaminobenzaldehyde.

Watson-Schwartz Test

for the differentiation between the presence of urobilinogen and porphobilinogen.

Mucopolysaccharides or glycosaminoglycans

• are a group of large compounds located primarily in connective tissue.

• Consists of a protein core with numerous polysaccharide branches.

• Mainly found in connective tissue.

Mucopolysaccharidoses (MPSs)

• Inherited metabolic disorders. 

• Prevent complete breakdown of the polysaccharide portion.

• Results in the accumulation of incompletely metabolized polysaccharides in the lysosomes of connective tissue cells and increased excretion in the urine.

• Dermatan Sulfate

• Keratan Sulfate

• Heparan Sulfate

Patients with Mucopolysaccharidoses (MPSs) will have chemicals frequently found in urine with is?

Hurler syndrome

• Inherited as a sex-linked recessive.

• Seen rarely on females.
  Severe intellectual disability.

• Abnormal skeletal structure.

• Mucopolysaccharides accumulate in the cornea.

• Short stature, mental retardation, prominent eyes, gape teeth, enlarged abdomen, and abnormal skeletal structure.

Sanfilippo syndrome

Clinical feature: Intellectual disability.

Cetyltrimethylammonium bromide (CTAB) Turbidity Test

Screening test for Sanfilippo syndrome

Melituria

is the presence of increased urinary sugar.

• Lactose (Lactosuria)

• Fructose (Fructosuria)

• Pentos (Pentosuria)

Other causes of melituria:

Galactosuria

• s the inability to properly metabolize galactose to glucose. 

• Galactose-1-phosphate uridyl transferase (GALT) deficiency.

• Galactokinase (GALK) deficiency

• UDP-galactose-4-epimerase deficiency

Galactosuria severe fatal symptoms:

Galactokinase (GALK) deficiency

Causes cataracts in adulthood

UDP-galactose-4- epimerase deficiency

Asymptomatic or mild symptoms

Clinitest Procedure (Copper Reduction Test)

• Screening test for Galactosuria

• Relies on the ability of glucose and other substances to reduce copper sulfate (redox reaction).